Bone health in young adults with type 1 diabetes and progressive eGFR decline.

BACKGROUND: Type 1 Diabetes (T1D) is associated with increased risk of fractures, worsened by presence of microvascular complications. This study's objective is to determine the impact of progressive decline in estimated glomerular filtration rate (eGFR) on bone biomarkers and bone microarchitecture in youth with T1D. METHODS: Slopes of eGFR were calculated using measures obtained at four timepoints from adolescence to young adulthood. Participants were identified as eGFR decliners if eGFR decreased ≥ 3ml/min/1.73m2/year. Bone health was assessed in young adulthood by high resolution peripheral quantitative computed tomography (HRpQCT Xtreme CTII) and bone biomarkers; osteocalcin, procollagen 1 intact n-terminal pro-peptide (P1NP), c-terminal telopeptide (CTX), and bone specific alkaline phosphatase. The relationship between diabetes duration, glycated hemoglobin, body mass index (BMI) and vitamin D level on bone biomarkers and microarchitecture was evaluated. Linear regression analysis was used for the statistical analysis in this study. RESULTS: Ninety-nine study participants were studied with longitudinal evaluation of eGFR over 7.4 ± 1.0 years with mean age of 14.7 ± 1.7 years at baseline. Cross sectional evaluation of bone was performed at 21.3 ± 2.1 years. 44% participants had eGFR decline and showed 5% higher cortical porosity diameter than non-decliners (p = 0.035). Greater diabetes duration was associated with higher trabecular separation (p = 0.004) and lower trabecular number (p = 0.01). Higher level of 25 hydroxy-vitamin D was associated with lower trabecular separation (p = 0.01). Elevated glycated hemoglobin (p = 0.0008) and BMI (p = 0.009), were associated with lower markers of bone formation. CONCLUSION: Mild increase in cortical porosity diameter was found in youth with T1D and eGFR decline, however, overall measures of bone microarchitecture on HR-pQCT were similar between both groups and there were no statistically significant changes in bone biomarkers. Hence, skeletal impairments were limited in youth with different eGFR trajectories near peak bone mass. Longitudinal HR-pQCT studies are needed to further understand the impact of eGFR decline on bone microarchitecture. Optimal glycemic control, normal BMI and vitamin D status were supported by this study as important markers for good bone health.

Metabolic and other morbid complications in congenital generalized lipodystrophy type 4.

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

Successful treatment of severe hypertriglyceridemia with icosapent ethyl in a case of congenital generalized lipodystrophy type 4.

OBJECTIVES: Congenital generalized lipodystrophy type 4 (CGL4) is a rare autosomal recessive condition with high rates of morbidity and mortality. It is a multisystem condition associated with ventricular tachyarrhythmia, congenital myopathy, hepatitis, and metabolic profile of severe hypertriglyceridemia and insulin resistance. Metreleptin is the first line treatment, however it is unavailable in several countries. Herein, we describe a unique presentation and treatment of CGL4. CASE PRESENTATION: A 16-year-old female presented with insulin resistant diabetes, and was later found to have myopathy, hypertriglyceridemia, nonalcoholic fatty liver disease, ventricular arrhythmias, and genetic confirmation of CGL4 due to homozygous change in CAVIN1 gene. She had severe hypertriglyceridemia, frequently >17 mmol/L, requiring several hospital admissions. To better control hypertriglyceridemia, in context of known congenital myopathy, we opted for treatment with icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), which reduces synthesis and enhances clearance of triglycerides. On this treatment, she was able to maintain stable triglyceride levels of 4 mmol/L. CONCLUSIONS: We present the first case report of a patient with CGL4, successfully treated for hypertriglyceridemia, with icosapent ethyl.